β-hydroxybutyrate as an Anti-Aging Metabolite

Abstract

The ketone bodies, especially β-hydroxybutyrate (β-HB), derive from fatty acid oxidation and alternatively serve as a fuel source for peripheral tissues including the brain, heart, and skeletal muscle. β-HB is currently considered not solely an energy substrate for maintaining metabolic homeostasis but also acts as a signaling molecule of modulating lipolysis, oxidative stress, and neuroprotection. Besides, it serves as an epigenetic regulator in terms of histone methylation, acetylation, β-hydroxybutyrylation to delay various age-related diseases. In addition, studies support endogenous β-HB administration or exogenous supplementation as effective strategies to induce a metabolic state of nutritional ketosis. The purpose of this review article is to provide an overview of β-HB metabolism and its relationship and application in age-related diseases. Future studies are needed to reveal whether β-HB has the potential to serve as adjunctive nutritional therapy for aging.

Keywords: aging; diseases; ketone body; metabolism; supplementation; β-hydroxybutyrate.

Figure 1

Structure of ketone bodies.

Figure 2

Pathways of ketogenesis in liver and ketolysis in extrahepatic tissues. Hepatic mitochondria act as the primary site for the synthesis of blood ketone bodies by using fatty acids-derived Ac-CoA which is generated by β oxidation. The following process requires four enzymes: ACAT, HMGCS2, HMGCL, and BDH1, and the intermediate product covers AcAc-CoA, HMG-CoA, and AcAc. β-HB is finally produced and released to the bloodstream and uptaken by extrahepatic tissues such as the brain, heart, neurons, kidneys, and muscles through MCT. Both β-HB and AcAc can be oxidized and converted to Ac-CoA and produce ATP via the TCA cycle as an alternative energy source. Abbreviations: AcAc, acetoacetate; AcAc-CoA, acetoacetyl CoA; ACAT, acetyl-CoA A acetyltransferase; Ac-CoA, acetyl CoA; BDH1, β-hydroxybutyrate dehydrogenase 1; β-HB, β-hydroxybutyrate; βox, β oxidation; CS, citrate synthase; FFA, free fatty acid; HMGCL, HMG-CoA lyase; HMGCS2, 3-hydroxymethylglutaryl-CoA synthase 2; HMG-CoA, 3-hydroxymethylglutaryl-CoA; MCT, monocarboxylate transporter; SCOT, succinyl-CoA:3-oxoacid CoA transferase; TCA, tricarboxylic acid.

Figure 3

The metabolic role of β-HB. β-HB acts as an energy substrate to regulate metabolic response, and serves as a signaling molecule to inhibit lipolysis, oxidative stress and improve neuroprotection, it also plays a role in epigenetic regulation including histone methylation, inhibition of HDACs, and histone lysine β-hydroxybutyrylation. Abbreviations: β-HB, β-hydroxybutyrate; HDAC, histone deacetylases.

Figure 4

Main epigenetic alterations of histone posttranslational modifications induced by β-HB. Histone posttranslational modifications which relate to the epigenetic regulation of β-HB mainly consist of histone methylation, acetylation, as well as a new type of histone lysine bhb. β-HB administration alters the modification of chromatin conformation through the epigenetic pathway. Chromatin structure is represented by DNA (blue line) organized in nucleosomes formed by core histones (grey square). Abbreviations: ac, acetylation; bhb, β-hydroxybutyrylation; β-HB, β-hydroxybutyrate; me, methylation.

Figure 5

Role of endogenous and exogenous nutritional ketosis in age-related diseases. Nutritional ketosis can be achieved endogenously through intermittent fasting, caloric restriction, ketogenic diets or exogenously with oral supplementation via ketone salts, ketone esters, medium-chain triglycerides, R, S-1,3- butanediol, and β-HB enantiomers, resulting in a therapeutic effect in several medical conditions, thereby targeting the underlying mechanisms of age-related diseases, such as cancers, neurological disorders, cardiovascular diseases, muscle dysfunction, inflammation, and metabolic syndrome, which may extend the healthy life expectancy. Abbreviations: β-HB, β-hydroxybutyrate.